1. Field of the Invention
The present invention relates to a fusion protein, more particularly, to a fusion protein for inhibiting cervical cancer induced or caused by HPV type 16 and pharmaceutical compositions thereof.
2. Description of Related Art
Currently, the incidence ratio of cervical cancer has remained high among all woman cancer patients. There are no any obvious symptoms of general variation of cervical epithelium or early cervical cancer. Although cervical cancer can be successfully treated in its early stages, prevention is still much better than treatment. Therefore, the researchers in this field have been making effort to find out the most efficient way to prevent cervical cancer.
It is already proved that human papillomavirus, HPV is highly related with cervical cancer. Some types (e.g. type 16, or 18) of DNA sequence of HPV had been found in cervical cancer cells, about 75%˜100%, but it is still not clear what the mechanism is in causing the cancer. Lately, research has found that the early gene product of virus—protein E6 and E7 of highly dangerous type 16, 18 and 31 of HPV easily combines with the product of genes Rb and p53 and thus reduce the ability of anti-tumor agent. This explains that HPV is not functioning alone when causing cancer but is assisted by environmental factors. Moreover, E7 protein expresses continuously in cervical cancer cells and carcinoma tissues. E7 protein also plays an important role in the process of maintaining shifted malignant tissue phenotype.
The cancer immune therapy is mainly displayed with cell-mediated immunization, assisted by humoral immunization. Cells involved in cell-mediated immunization are cytotoxic T lymphocytes (CTL), NK and macrophages. CTL is triggered by interlukin-2, and then identified by T cells. The major histocompatibility complex (MHC) on the cancer cells with antigen present appears and releases lysozyme to destroy the cancer cells and restrain the proliferation of cancer cells. CTL protection is proved to inhibit cancers caused by HPV. Therefore if it is possible to induce the proliferation of the HPV-antigen-specific CTL, for example, CD 8+ T lymphocytes, by enhancing complexes of HPV antigen and MHC class I presenting on cancer cells, the strategy of CTL induction with E7 antigen can be able to control carcinoma cell directly and beneficial for immunological prevention and treatment.
It is proved by research that cervical cancer is able to be prevented by vaccine injection. E7 proteins of HPV are highly common in carcinoma tissues or the tissues before carcinoma damage, therefore, E7 protein has the potential for developing as a vaccine. Basically, HPV type 16 and HPV type 18 are serious causes of not only cervical cancer, they are also dangerous factors for inducing lung cancer in females. The carcinogenic proteins E6 and E7 can be transferred to lungs through the circulation of blood and they decompose the anti-tumor proteins produced by gene Rb and p53. Once the anti-tumor genes or the proteins produced by them are deactivated, cancer cells show up. Though the present DNA vaccine does have a long term effect, on the other hand, it has high production costs. The main factor of restrained development in the DNA vaccine is the highly dangerous nature of the virus itself, which mutates easily. Furthermore, when applying E7 protein in gene therapy to cervical cancer, the induced immune response is usually induced weakly because of the weak antigen character of E7 protein of HPV virus. The effect of the prophylaxis and the therapy of cervical cancer are not able to be evaluated because of frail immune response.
Generally, the specific antigen of cancer cells needs to be modified and combined with MHC-I then presented to the cell surface in order to trigger the CD8+ cells and elicit cell-mediated system. The research shows that the HPV type 16 E7 gene can be found in cervical cancer tissues but there is a lack of the specific MHC-I complex to present to the cell surface for showing E7 antigen. Therefore, HPV type 16 E7 protein will not be present to or initiate the cellular immune system of the host cell and then HPV escapes from the detection or monitoring of host. Usually, when E7 protein is injected in vivo, it is considered as external antigens. The E7 vaccination can only be induced the humor immune response thus lowering the effect to elicit cell-mediated immunity. Hence, it is necessary to develop a transportation system of sending the intact foreign protein into cytoplasm and induce effective immune response.
Therefore, it is desirable to provide an fusion protein for inhibiting cervical cancer to mitigate and/or obviate the aforementioned problems.